Isosorbide dinitrate and glyceryl trinitrate: Demonstration of cross tolerance in the capacitance vessels

lsosorbide Dinitrate and Glyceryl Trinitrate: Demonstration of Cross Tolerance in the Capacitance Vessels DANTE E. MANYARI,

MD, ELDON R. SMITH, MD and JANICE SPRAGG, RT

Cross tolerance to the arterial effects of sublingual glyceryl trinitrate (GTN) has been demonstrated in subjects taking oral isosorbide dinitrate (ISDN). To determine if cross tolerance also develops in the venous system, the effects of 0.6 mg of GTN on venous capacitance were assessed before (stage A) and during (stage B) therapy with ISDN. Venous capacitance was assessed using the radionuclide blood pool method, with relative changes in regional blood volume measured in the forearm in 6 patients and the splanchnic circulation in 4 patients. Heart rate, blood pressure and blood volume were measured before and at l-minute intervals for 10 minutes after GTN; there was less than 2% variability in regional blood volume during 6 control measurements. During stage A, 5 minutes after GTN, systolic blood pressure (mean f standard deviation) decreased by 14% (from 125 f 15 to 107 f 19 mm Hg, p
66 f 14 to 80 f 17 beats/Win, p
Partial circulatory tolerance to organic nitrates develops rapidly in humans. l-l5 Similarly, cross tolerance between glyceryl trinitrate (GTN) and other organic nitrates has been described to occur at usual therapeutic doses.1~7~gJ0 Although circulatory tolerance and cross tolerance in terms of blood pressure and heart rate have been demonstrated,1>7>gJ1-13 limited data are available regarding nitrate cross tolerance in the venous capacitance vessels,10J4J5believed to be the site of predominant nitrate action. Furthermore, the few studies have yielded conflicting results. Much of the available information regarding the control of capacitance vessels has been obtained with plethysmographic or gravimetric techniques,lsJ7 which measure shifts in regional blood volume. These meth-

ods, however, do not separate changes in the volume of capacitance vessels from those in the extracellular compartment,ls a differentiation that may be especially important when performing prolonged experiments. Moreover they are not suitable for the study of regions such as the splanchnic circulation, usually being confined to study the limbs. Recently, quantitative regional blood pool imaging has been used to measure regional volume changes in the capacitance vessels of limbs, as well as other regions including the splanchnic circulation.1g-24Using this latter technique, this study assesses whether cross tolerance between isosorbide dinitrate (ISDN) and GTN develops in the venous system. Methods Patient group: Fourteen patients with stable, exercise-

From the Cardiology Division, Department of Medicine, University of Calgary and the Cardiovascular Laboratories, Foothills Hospital, Calgary, Canada. This study was supported in part by the Alberta Heart Foundation, Calgary, Alberta, Canada. Manuscript received October 19, 1984; revised manuscript received January 2, 1985, accepted January 4, 1985. Address for reprints: Dante E. Manyari, MD, Cardiology Division, Foothills Hospital, 1403-29th Street, N.W., Calgary, Alberta, Canada T2N 2T9.

induced angina entered the study, although 4 could not complete all stages of the protocol. Two patients could not tolerate oral ISDN becauseof headachesand 2 had progressive angina not controlled by nitrates and eventually underwent coronary angioplasty. The study group thus included 10 patients (8 men, 2 women), aged 43 to 80 years (mean $1). Coronary artery disease was confirmed by angiography m 4 pa927

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tients; 3 patients had sustained a previous myocardial infarction. No patient was hypertensive or had clinical evidence of congestive heart failure; all remained stable throughout the study period. Except for sublingual GTN, no patient received vasoactive drugs before the study and GTN was not used within 4 hours of hemodynamic measurements. Study design: The hemodynamic response to 0.6 mg of sublingual GTN was assessedon the first day without any other medication (stageA) and again during sustained therapy with oral ISDN for 4 weeks (stage B). Hemodynamic measurements included regional blood volume changes,heart rate and blood pressure. Regional blood volume was measured every minute for 6 minutes before GTN, at l-minute intervals for 7 minutes and at 10 minutes after GTN. Heart rate and blood pressure were recorded twice before and every minute for 10 minutes after GTN administration. After measurements during stage A were completed, patients received oral ISDN every 6 hours, 10 mg for 3 days, 20 mg for 3 days then 30 mg every 6 hours for 4 weeks.At the end of week 4, all measurements were repeated (stage B) 5 to 6 hours after the morning dose of ISDN. All measurementswere made between 10 and 11 AM, in the fasting state and in the supine position. Radionuclide blood volume measurements: Equilibrium blood pool radionuclide angiography was used to measure the changes in regional blood volume in the left forearm in 6 patients and in the splanchnic circulation in 4 patients (Fig. 1).

In vivo labeling of red blood cells with 25 mCi of technetium-99m was achieved by standard techniques. To minimize the amount of circulating free technetium-99m, initial scintigrams were recorded 45 to 60 minutes after labeling. To keep spontaneous physiologic variability to a minimum, all measurements were made after a 12-hour fast and after a 30minute rest period in the supine position in a laboratory devoid of significant visual or auditory stimuli. Anterior views of the abdomen were used to image the splanchnic circulation. Scintigrams of the left forearm were recorded with the limb extended 60’ laterally and resting over the camera detector, which was positioned facing up at the level of the imaging table. Care was taken to maintain the same patient-camera position during each session. Static scintigrams were recorded for 30 secondsat intervals described above, using a standard gamma camera interfaced to a general nuclear medicine computer system. To define the same anatomic segments in consecutive scintigrams, lead markers taped to the skin for the duration of each sessionwere used as reference points to select identical regions of interest (Fig. 1). Count rates obtained after the first acquisition were corrected for physical decay for technetium-99m. Because the aim of this study was to detect relative blood volume changes, background was not taken into account in the calculations because it was considered to remain constant in successive scintigrams. Statistical analyses: Group results of each measurement were analyzed by 2-way analysis of variance followed by the Tuckey’s procedure when appropriate. Paired t tests were used when comparing a given measure between stages A and B. Results

Heart rate and blood pressure: After GTN, mean ( f standard deviation) heart rate increased significantly (p
*---Stage

FIGURE 1. Analog blood pool images of the forearm (A) and abdomen (B) recorded after red blood cell labeling with technetium-99m, with (bottom) and wtthout (top) the assigned regions of interest. Lead markers (arrows) taped to the skin in a plane parallel to that of the gamma camera collimator were used to define the same anatomic regions of interest in successive scintigrams. Changes in regional count rate, corrected for physical decay of technetium99m, were used to assess regional blood volume changes in the forearm and the splanchnic circulation. In the forearm, the region studied was that delineated by 2 strips of lead markers (A). In the abdomen, the splanchnic region of interest was selected away from the abdominal large vessels, kidneys, bladder or stomach, as a rectangle of the same size (measured in pixels) for a given patient study (B).

4

A

T

I

I -6

-4

-2

I 0 TIME

I 2 (minutes)

T -

I

I

4

6

c

’

10

FIGURE 2. Croup heart rate (mean f standard error of the mean) changes before and after nitroglycerin administration during a control period (stage A) and after 4 weeks of treatment wlth tsosorbide dintkate (stage B). Patients received 0.6 mg of sublingual nitroglycerin at time 0. l ‘p CO.05; t p
April 1, 1965

patient, with group heart rate being the highest at 3 to 4 minutes after GTN. Similarly, average systolic blood pressure decreased significantly after administration of GTN both during stage A (from 125 f 15 to 107 f 19 mm Hg, p 0.05), and the maximal decrease after GTN was greater (p cO.05) during stage A than during stage B. The magnitude and timing of the maximal blood pressure changes varied from patient to patient, with the lowest group values observed at 4 to 5 minutes after GTN. Venous capacitance: Group results of relative changes in regional blood volume are shown in Figure 4. Control measurements were remarkably constant; the corrected number of counts varied by less than 2% during each of the 6 baseline measurements. During stage A, mean regional blood volume increased by 11% at minute 5 after GTN (p
d 0

90 t

.---Stage

A

o-Stage

B

j: c, I ! I 1 I 1 , ’ v) -6

-4

-2

0 2 TIME (minutes)

4

6

10

FIGURE 3. Group systolic blood pressure (mean f standard error of the mean) changes before and after nitroglycerin administration during a control period (stage A) and after 4 weeks of treatment with isosorbkfe din&rate (stage B). Patients received 0.6 mg of sublingual nitroglycerin at time 0. p <0.05; + p
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develops in the venous as well as the arterial system in humans. Our results do not address the question of the development of tolerance to ISDN nor the relation of this phenomenon to clinical efficacy. Although many investigators have studied the phenomenon of cross tolerance between various prepara-

12 s w 10 P 2

*---Stage

A

O-Stage

0

a

Ll, -6

I I I I!

1 I

-2

0 2 TIME (minutes)

-4

I I I I ,,+-I 4

6

10

FIGURE 4. Group regional blood volume (mean f standard error of the mean) changes before and after nitroglycerin administration during a control period (stage A) and after 4 weeks of treatment with isosorbide dinitrate (sfage B). Patients received 0.6 mg of sublingual nitroglycerin at time 0. p <0.05; t p
24

r

! I I I 11 1 I I I I -6

-3

0

3

6

9

TIME (minutes) FIGURE 5. Individual changes in relative regional blood volume before and after nitroglycerin (GTN) administration during stage A. Values are shown before GTN at l-minute intervals, at maximal effect and 10 minutes after GTN. The maximal change in regional blood volume varied considerably in both magnitude and time of occurrence (between 3 and 7 minutes after GTN). A = regional abdominal counts (see text).

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tions of organic nitrates, they have limited their investigations to the study of changes in heart rate, blood pressure, exercise capacity and exercise-induced STsegment depression on the electrocardiogram.l?7*9-15 Only 2 previous investigations have addressed the question of cross tolerance between ISDN and GTN in the venous system.1°J4Zelis and MasonlO measured the effects of sublingual GTN on calf blood flow, vascular resistance and venous volume in 6 subjects before and after 6 to 8 weeks of oral ISDN.lO They found that GTN increased the capacitance volume by 9% before ISDN, whereas no change was demonstrated during chronic ISDN administration. The abolition of the venodilator effect of GTN during ISDN therapy was, however, not paralleled in the arterial system, because the blood pressure, vascular resistance and blood flow changes produced by GTN were similar before and after chronic ISDN administration. These investigators used the venous occlusion technique with a mercury-in-rubber strain gauge plethysmograph to measure calf venous volume and volume changes. Although our results generally agree with those of Zelis and Mason10 with regard to the venous system, we and others1~2~7~g also noted the development of significant cross tolerance between ISDN and GTN in the arterial system. Different patient groups, different techniques to assess venous capacitance volume or different protocols may account for these discrepancies. In another study, Schlup et all4 studied 8 young healthy subjects (mean age 28 years) and 10 older patients with coronary artery disease (mean age 62 years), using “the quotient of maximal systolic and minimal diastolic flow calculated oscillometrically” as a measure of vasodilatation of capacitance vessels. Three days of therapy with ISDN produced a marked and significant attenuation of the venodilator effect of GTN but only in young healthy subjects. In older patients with coronary artery disease, the venodilator effect of GTN was similar before and during ISDN therapy. Cross tolerance to the tachycardic effects of GTN was observed only in patients with coronary artery disease and not in normal subjects. l4 Based on our results, we cannot explain these rather unusual findings, but again wonder if the different techniques used to study venous capacitance, as well as the short duration of “chronic” ISDN therapy, may account for the different results. More difficult to explain is the discrepancy between the results obtained by Zelis and MasonlO and Schlup et al,14becausesimilar techniques to assessvenous volume changes were used in both studies. In the present investigation, radionuclide blood pool scintigraphy was used to measure regional blood volume changes. In this technique, blood pool scintigraphy is achieved by labeling the red blood cells with technetium-99m. A scintillation camera then quantifies the external radioactivity,

which is proportional

to the in-

travascular volume of the imaged region. Contrary to plethysmographic

or gravimetric

techniques,lsJ7

which

detect changes in volume in the intravascular and extravascular compartments, only changes in intravascular volume are detected by the radionuclide

blood

pool method. This consideration may make the radionuclide method preferable for estimating volume changes in the capacitance vessels.21 We elected to study regional blood volume changes in either the forearm or splanchnic circulations since preliminary experimental and clinical observations in our laboratory22,23*25indicate that the effects of GTN are directionally similar in both regions. However, it is not clear that a given increase in blood volume, in percent units, represents an equivalent venodilatory response in these 2 regions. In patients with overt heart failure, venodilation after GTN may be more marked than in patients without heart failure.26 Moreover, it is possible, as suggested by some workers,27p28that an increase in venous capacitance in the splanchnic region may not necessarily reflect a direct venodilator effect. Rather, in some instances it may be caused by passive blood pooling as a result of arteriolar vasodilation. However, independent of patient group or mechanisms of action, our study shows that the increase of venous capacitance after GTN is attenuated after a 4-week treatment with ISDN. Clinical implications: GTN remains the cornerstone of therapy for angina pectoris. If the major mechanism of action is venodilatation with a resultant decrease in myocardial oxygen demand, the demonstration of partial cross tolerance with ISDN may have important clinical implications. Thus, patients receiving chronic ISDN (or possibly other long-acting nitrate preparations) may require larger dosesof GTN to obtain angina prophylaxis or relief. Whether partial venous cross tolerance also occurs in patients with congestive heart failure is not established, although if present, the implications to the therapy of angina might be similar. These theoretic considerations require clinical testing. Acknowledgment: We thank Dr. I. Belenkie for his support during all phases of this investigation. We are grateful to Kathy Will and Perry Anderson for their technical assistance, to Sue Denyar and Isabella Bishop for preparing the manuscript and to Debra Anglin for editorial assistance. References 1. Thadani U, Manyarl D, Parker JO, Fung HL. Tolerance to the circulatory effects of oral isosorbiie dinitrate. Rate of development and cross-tolerance to glyceryl trinitrate. Circulation 1980;61:526-535. 2. Thadanl U, Fung H, Darke AC, Padox JD. Dral isosorbide dir&ate in angina pectoris. Comparison of duration of action and dose response relationship during acute and sustained therapy. Am J Cardiol 1982;49:411-419. 3. Taucherl M, Jansen W, Osterspey A, Fuchs M, Hombach V, Hllger HH. Hemodynamic effects of 5-isosorbii mononitrate during acute and chronic administration. In: Kaltenbach M, Kober G. eds. Nitrates and Nitrate Tolerance in Angina Pectoris. Darmstadt, Steinkopff, 19X%43-56. 4. Blaslnl R, BriigmaM U, Marines A, Froer KL, Hall D, Rudolph W. Wirksamkeit von ISDN in retardierter Form bei Langzeitbehandlung. Herz 1980;5:298-305. 5. Needleman P. Tolerance to the vascular effects of glyceryl trinitrate. J Pharmacol Exp Ther 1970;171:98-102. 6. Fun9 HL, McNlff EF, Rugglrello D, Darke A, Thadanl U, Parker JO. Kinetics of isosorbide dinitrate and relationships to pharmacological effects. Br J Clin Pharmacol 1981;11:579-590. 7. Schelllng J, Lasagna L. A study of cross-tolerance to circulatory effects of organic nitrates. Clin Pharmacol Ther 1967;8:256-260. 8. Hauf OF, Bubenhelmer P, Roskamm H. Treatment of congestive heart failure with vasodilators: comparison of acute and long-term effects of various agents. In: Kaltenbach M, Kober G, eds. Nitrates and Nitrate Tolerance in Angina Pectoris. Darmstadt, Steinkopff. 1983:77-64. 9. Lee 0, Mason DT, DeMarla AN. Effects of long-term oral administration of isosorbii dir&rate on the antiinginal response to nitrqlycerin. Absence of nitrate cross tolarance and self tolerance shown by exercise testing. Am

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J Cardiol 1978;41:82-87. 10. Zelte R, Maeon M. lsosorbtde dinitrate. Effect on the vasodilatcr response to nitroglycerin. JAMA 1975;234: 168-170. 11. Francloea JA, Cohn JN. Sustained hemodynamic effects without tolerance during long-term isosorbide dinitrate treatment of chronic left ventricular failure. Am J Cardiol 1980;45:648-654. 12. Becker HJ. Walden 0. Kalterbach M. Gibt es eine “tachvohvlaxie” bzw. eine Gew&nung bei &r Sehandlung der Angina pectoris u’nb Nitroglycerin. Verh Dtsch Ges Inn Med 1976;62:1208-1210. 13. Abrams J. Nitrate tolerance and dependence. Am Heart J 1980;99:113.“” IL.x 14. Schlup P, Zatti CH, Studer H. Toleranzentwicklung gegenuber den haemodynamischen Wirkungen von Nitroglyzerin. Schweiz Med Wochenschr 1980:110:1927-1934. 15. Kaiser H, Sold 0, Schrader J, Kreuzer H. Development of tolerance and peripheral hemodynamic effects of molsidomine. In: Kaltenbach M, Kober G, eds. Nitrates and Nitrate Tolerance in Angina Pectoris. Oarmstadt, Steinkopff, 1983:101-106. 16. Abboud FM, Schmld PG, Ecksteln JW. Vascular responses after alpha adrenergic receptor blockade. I. Responses of capacitance and resistance vessels to noreoineohrine in man. J Clin Invest 1968:47:1-9. 17. Samueloff S, B&vGrd BS, shepherd JT. Temporary arrest of circulation to a limb for the study of venomotor reactions in man. J Appl Physlol 1966;21:341-346. 16. Ablad B, Mellander S. Comparative effects of hydralazine, sodium &rate atxi acetylcholine on resistance and capacitance blood vessels and capillary filtration in skeletal muscle in the cat. Acta Physiol Stand 1963;58:319329. 19. Rutlen D, Wackers F, Zaret BL. Radionuclide assessment of peripheral

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intravascular capacity: a technique to measure intravascular volume changes in the capacitance circulation in man. Circulatiion 1981;64: 146-152. Clements I, Strelow D, Becker 0, Vietstra-Brown M. Radionuclkte evaluation of peripheral circulatory dynamics: new clinical blood pool sclntlgraphy for measuring limb venous volume, capacitance, capacity, and blood volume. Am Heart J 1981:102:960-983. Dltlrich HC, Slutsky RA. Radionuclide analysis of the forearm venous pressure-volume relationship. Response to nitroglycerin. Am Heart J 1984;107:733-737. Smlselh OA, Klngma I, Manyarl DE, Smlth ER, Tyberg JV. Mechanism of nitroglycerin induced blood volume redistribution (abstr). JACC. in press. Smlseth OA, Yanyarl DE, Llma JA, Klngma I, Smlth ER, Tyberg JV. Interaction between splanchnic venous capacitance and pericardial presstze (abstr). Eur Heart J 1984:5:suppl 1:156. Bell L, Zaret B, Rutlen D. Quantitative radionuclide assessment of the splanchnic capacitance vasculature: validation of a new method (abstr). Circulation 1983;68:suppl lll:lll-83. Smith ER, Smlseth OA, Klngma I, Manyarl DE, Belenkle I, Tyberg JV. Mechanism of action of nitrates. Role of changes in venous capacitance and in the left ventricular diastolic oressure-volume relation. Am J Med 1984;76(6A):l4-21. Lees D, Schnekter R, Schorner W. Changes in regional bcdy blood volume caused bv nitroolvcerin. 2 Kardiol 1963:72:suooI 3:29-32. BteoksbiGA, &!&Id DE. Release of blood fro% the splanchnic circulation in dogs. Circ Res 1972:31:105-l 18. Packer M. Conceptual dilemmas in the classification of vasodilator drugs for severe chronic heart failure. Advocacy of a pragmatic approach to the selection of a therapeutic agent. Am J Med 1984;76(6A):3-13.